Ultrasound based method and apparatus for stone detection and to facilitate clearance thereof

ABSTRACT

Described herein are methods and apparatus for detecting stones by ultrasound, in which the ultrasound reflections from a stone are preferentially selected and accentuated relative to the ultrasound reflections from blood or tissue. Also described herein are methods and apparatus for applying pushing ultrasound to in vivo stones or other objects, to facilitate the removal of such in vivo objects.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/928,440, filed Oct. 30, 2015, which is a continuation of U.S. patentapplication Ser. No. 13/092,811, filed Apr. 22, 2011 (now U.S. Pat. No.9,204,859), which claims the benefit of U.S. Provisional PatentApplication No. 61/474,002, filed Apr. 11, 2011, and U.S. ProvisionalPatent Application No. 61/326,904, filed Apr. 22, 2010, all of which areincorporated herein by reference in their entireties.

STATEMENT OF GOVERNMENT LICENSE RIGHTS

This invention was made with government support under DK043881 andDK086371, awarded by the National Institutes of Health and SMST01601,awarded by the National Space Biomedical Research Institute. Thegovernment has certain rights in the invention.

BACKGROUND

Residual stone fragments such as kidney stones often remain aftercurrent methods for stone treatment, such as extracorporeal shockwavelithotripsy, ureteroscopic lithotripsy, and percutaneousnephrolithotomy. In some cases such fragments remain in the lower poleof the kidney. New stones may grow from these fragments, and suchfragments have been reported to contribute to a 50% recurrence of kidneystones within 5 years. Thus, improved methods for detecting stones andfor facilitating stone clearance from the body are needed.

SUMMARY

It is thus one object of the invention to provide an ultrasounddetection method and system for stones in a mammal in which ultrasoundreflections from stones are selected and displayed preferentiallyrelative to ultrasound reflections from blood or other tissue.

It is another object of the invention to provide an ultrasound detectionmethod and system for stones in a mammal in which ultrasound reflectionsfrom stones are selected and displayed preferentially relative toultrasound reflections from blood or other tissue, wherein the appliedultrasound used for stone detection is B-mode ultrasound.

It is another object of the invention to provide an ultrasound detectionmethod and system for stones in a mammal in which ultrasound reflectionsfrom stones are selected and displayed preferentially relative toultrasound reflections from blood or other tissue, wherein the appliedultrasound used for stone detection is Doppler ultrasound.

It is another object of the invention to provide an ultrasound detectionmethod and system for stones in a mammal in which ultrasound reflectionsfrom stones are selected and displayed preferentially relative toultrasound reflections from blood or other tissue, wherein the appliedultrasound used for stone detection is Doppler ultrasound, and thepreferentially selected reflections are those associated with theDoppler ultrasound twinkling artifact.

It is another object of the present invention to apply an ultrasonicpushing force to an in vivo stone in a mammal to facilitate clearance.

It is another object of the present invention to apply an ultrasonicpushing force to a stone to facilitate clearance while using detectionof the stone.

It is another object of the present invention to apply an ultrasonicpushing force to a stone to facilitate clearance while using ultrasonicdetection of the stone.

In accordance with one aspect of the present invention, ultrasound isused to apply a pushing force to a stone in vivo to facilitateclearance, without causing undue damage to the surrounding tissue. Theapplied pushing ultrasound can be of lower pressure amplitude thanultrasound used in shock wave lithotripsy (“swl”). It also can have ahigher duty cycle to create a sustained force that can reposition astone.

In another aspect of the present invention, the pushing ultrasound isapplied in conjunction with detection ultrasound, to allow for detectionof the stone such as by visualization on an ultrasound display monitor,or by aural detection. In one embodiment, the detection ultrasound maybe a variant of B-mode ultrasound; in another embodiment the detectionultrasound may be a variant of Doppler ultrasound. In a preferredembodiment of the invention, the ultrasound reflections from the stonesare selected and displayed preferentially relative to ultrasoundreflections from blood and tissue. Where Doppler ultrasound is used, inone embodiment of the invention the twinkling artifact can be used tofacilitate detection of the stone. In one aspect of the invention, suchdetection ultrasound is used to locate a stone prior to the applicationof the pushing ultrasound. In another aspect of the invention, thedetection ultrasound is used in real time to monitor the movement of thestone during the application of the pushing ultrasound.

In one embodiment of any aspect of the present invention, the pushingultrasound is applied as a focused beam directed along a propagationaxis directed to one or more stones or fragments. In another embodimentof any aspect of the invention the pushing ultrasound is applied in anunfocused or weakly focused mode to a general region of anatomy wherestones are likely to occur. For example, such unfocused or weaklyfocused ultrasound energy could be applied generally to a region of akidney such as the lower pole region to stir up any fragments that mightbe located therein, thereby facilitating clearance.

In one embodiment of the invention the methods and systems are used tofacilitate the removal of stones, such as stones ranging from about 1 toabout 10 mm in diameter. In another embodiment, the in vivo stone isfragmented before applying the pushing ultrasound. Such fragmenting canbe carried out by any suitable technique, including but not limited toextracorporeal shockwave lithotripsy, ureteroscopic lithotripsy, andpercutaneous nephrolithotomy. In another embodiment of any aspect of theinvention, the in vivo stone is fragmented after applying the pushingultrasound, wherein the in vivo stone can be first pushed toward anexit, so that once fragmented, the fragments are more likely to beeasily cleared. In another embodiment of the invention, pushingultrasound is used to induce displacement of stones that may be largerthan 10 mm in diameter. For example, displacement of larger stones atthe entrance to the ureteropelvic junction (UPJ) would have considerableclinical benefit in relieving pain.

In an exemplary embodiment of the invention for facilitating removal ofin vivo stones, detection ultrasound is used to locate the in vivostone, and pushing ultrasound is used to cause the located in vivo stoneto move toward an exit, which exit can be either naturally occurring orprovided surgically.

In a further embodiment, the step of using pushing ultrasound to causethe in vivo stone to move is implemented using a quantity of pushingultrasound sufficient to cause the in vivo stone to move at a rate of atleast about one centimeter per second.

In another embodiment, the pushing ultrasound has a pulse duration ofabout one hundred times that of the detection ultrasound.

In another aspect of the invention the amount of pushing ultrasound usedis calculated based on a numerical simulation program, such thatultrasound exposures can be determined for each unique stone andanatomical situation. In such calculations the radiation force on thestone is found using elasticity equations based on the predicted in situparameters of ultrasound field and expected mechanical properties of thestone, such as density, shear and compressional moduli.

In a further aspect, the present invention provides non-transitorycomputer readable storage media, for automatically carrying out themethods of the invention on a device, such as an ultrasound device orsystem according to the invention.

In a further aspect, the system of the present invention displays thestone as it is pushed in real time and tracks the stone motion,continually refocusing the pushing force on the moving stone.

This Summary has been provided to introduce a few concepts in asimplified form that are further described in detail below in theDetailed Description of the Invention. However, this Summary is notintended to limit key or essential features of the claimed subjectmatter.

DESCRIPTION OF THE DRAWINGS

Various aspects and attendant advantages of one or more exemplaryembodiments and modifications thereto will become more readilyappreciated as the same becomes better understood by reference to thefollowing detailed description, when taken in conjunction with theaccompanying drawings, wherein:

FIG. 1 schematically illustrates a first exemplary embodiment employingthe concepts disclosed herein, wherein detection ultrasound is used tolocate an in vivo object, and pushing ultrasound is used to move the invivo object in a desired direction while detecting the movement of theobject;

FIG. 2 schematically illustrates an exemplary system employed tovisualize an in vivo object using detection ultrasound, and to move thein vivo object, using pushing ultrasound;

FIG. 3 is a flow chart of exemplary steps employed to visualize an invivo object using detection ultrasound, and to move the in vivo object,using pushing ultrasound;

FIG. 4 schematically illustrates an empirical system employed to verifythat pushing ultrasound can be used to move an in vivo object, and thatsuch motion can be visualized in real-time;

FIG. 5A illustrates the basic components of a system for practicing theinvention;

FIG. 5B is a schematic illustration of ultrasound radiation emanatingfrom and being reflected back toward a transducer;

FIG. 5C is a flowchart of a system for B-mode ultrasound imaging inaccordance with the prior art;

FIG. 6 is a flowchart of one embodiment of the present invention usingB-mode ultrasound to preferentially identify and display an image of astone relative to blood or tissue in which the reflected signals ofgreatest amplitude or intensity are selected and labeled with color onthe display;

FIG. 7 is a flowchart of one embodiment of the present invention usingB-mode ultrasound to preferentially identify and display an image of astone relative to blood or tissue using the shadow created when B-modeultrasound encounters a stone;

FIG. 8 is a flowchart of one embodiment of the present invention usingB-mode ultrasound to preferentially identify and display an image of astone relative to blood or tissue and using a spatial derivative of thedata collected to determine the presence of a stone;

FIG. 9 is a flowchart of a system for Doppler ultrasound imaging inaccordance with the prior art;

FIG. 10 is a flowchart of one embodiment of the present invention usingDoppler ultrasound to preferentially identify and display an image of astone relative to blood or tissue and wherein one or more units ofpulses, frames or volumes in the ensemble is multiplied by a selectedfactor;

FIG. 11 is a flowchart of one embodiment of the present invention usingDoppler ultrasound to preferentially identify and display an image of astone relative to blood or tissue and relating to detection of largechanges in amplitude among units of pulses, frames or volumes of anensemble;

FIG. 12 is a flowchart of one embodiment of the present invention usingDoppler ultrasound to preferentially identify and display an image of astone relative to blood or tissue and relating to calculation of thevariance of the signal;

FIG. 13 is a flowchart of one embodiment of the present invention usingDoppler ultrasound to preferentially identify and display an image of astone relative to blood or tissue and relating to detection of thestrength of the noise and not the signal from the autocorrelation,optionally with a wall filter;

FIGS. 14A and 14 b are illustrations of a device used in the embodimentof Example 2 of this application;

FIGS. 15A and 15B are representative images of ultrasonic propulsion ofa stone in accordance with Example 2 of this application; and

FIGS. 16A-16C are representative histology slides from a control, andexposure to 325 W/cm² and exposure to 1900 W/cm² of the sample ofExample 2 of this application.

DETAILED DESCRIPTION

Exemplary embodiments are illustrated in referenced Figures of thedrawings. It is intended that the embodiments and Figures disclosedherein are to be considered illustrative rather than restrictive. Nolimitation on the scope of the technology and of the claims that followis to be imputed to the examples shown in the drawings and discussedherein. Further, it should be understood that any feature of oneembodiment or aspect disclosed herein can be combined with one or morefeatures of any other embodiment or aspect that is disclosed, unlessotherwise indicated.

The following additional definitions shall apply in this application:

“Stone”—any piece of calculus material such as may be found, forexample, in an organ, duct or vessel of a mammal, and including stones,stone fragments, and stone dust that may result from the application ofshock waves or other therapeutic procedures; and equivalent embeddedobjects for which movement or displacement is desired.

Pressure amplitude—the maximum displacement of the acoustic pressurefrom ambient.

Duty cycle (also referred to as duty factor)—pulse duration divided bypulse repetition frequency times 100%.

Power—Energy per time, for both electric and acoustic power. Electricpower excites the transducer element as a source; acoustic power is inthe acoustic wave generated by the transducer element.

Intensity—power transmitted through a cross-sectional area. Crosssectional area can be determined as the beamwidth of the acoustic beam;or as applied to a stone cross sectional area can be the cross sectionof the stone.

Pulse—an acoustic wave of a certain duration. A single pulse encompassesone or several cycles of pressure oscillation at the center frequency.The excitation of one or more elements in the transducer generates apulse. Pulses in B-mode tend to be 1-2 cycles and pulses in Doppler tendto be 3-7 cycles. The pulse created by a shock wave lithotripter tendsto be 1 cycle.

Doppler Ultrasound—a mode or several modes of ultrasound imaging used todetect blood flow.

B-mode ultrasound—a mode of ultrasound used to create an image ofanatomical structures.

Ultrasound waves can be characterized by any one or more of thefollowing intensity parameters:

Temporal peak, I_(TP), is the highest instantaneous intensity in thebeam.

Temporal average, I_(TA), is the time averaged intensity over the pulserepetition period.

Pulse average, I_(PA), is the average intensity of the pulse.

Spatial peak, I_(SP), is the highest intensity spatially in the beam.

Spatial average, I_(SA), is the average intensity over the beam area.

Spatial average-temporal average intensity, I_(SATA), is the acousticpower contained in the beam in watts averaged over at least one pulserepetition period, and divided by the beam area.

Spatial average-pulse average intensity, I_(SAPA)=I_(SATA)/duty cycle,where I_(PA)=I_(TA)/duty cycle.

Spatial peak-temporal average intensity,I_(SPTA)=I_(SATA)(I_(SP)/I_(SA).

Spatial peak-pulse average intensity,I_(SPPA)=I_(SATA)(I_(SP)/I_(SA))duty cycle.

Pushing Ultrasound

Acoustic radiation force results from the transfer of acoustic wavemomentum to an absorbing or reflecting object. In the context of thepresent invention, acoustic radiation of selected pressure amplitude,duration, frequency, and duty cycle is applied to a stone which absorbsthe momentum to facilitate non-invasive repositioning of the stone, toallow removal, passage, or further treatment. Such acoustic radiation isreferred to herein as pushing ultrasound.

The pushing ultrasound of the system of the present invention willoperate at I_(SPTA)>3 W/cm² in situ. In one preferred embodiment, thepushing ultrasound of the present invention has a time averaged spatialpeak intensity of I_(SPTA)>4 W/cm². A higher pressure can allow for ashorter pulse time or a longer time between pulses. In some embodimentsof the invention, the longer time between pulses can be used toreal-time imaging between pushing pulses. This is in comparison todiagnostic ultrasound approved for use in the U.S., which must operateat I_(SPTA)<720 mW/cm² (and MI<1.9) and I_(SPPA)<190 W/cm², and shockwave lithotripsy and physical therapy ultrasound, which operate atI_(SPTA)<3 W/cm².

Further in accordance with the present invention, pushing ultrasoundwaves have pressure amplitudes in the range of between about 5 MPa andabout 30 MPa, preferably between about 10 MPa and 20 MPa, and mostpreferably between about 13 MPa and 18 MPa. As is known in the art,detection ultrasound waves generally have a pressure amplitude in therange of about 5 MPa or less, while ultrasound waves used in shock wavelithotripsy (“swl”) as approved for use in the United States haveamplitudes of at least about 30 MPa as measured in water. The highpressures of lithotripsy are necessary to break the stones.

The pushing ultrasound waves used in the present invention also aredistinguished from other ultrasound waves by the number of cycles perpulse, and by the duty cycle. B-mode ultrasound for detection and shockwave ultrasound for lithotripsy each use a single pulse per cycle; whilepushing ultrasound waves used in the present invention use more than onepulse per cycle, typically more than about 5-10 pulses per cycle.Pushing ultrasound waves for use in the present invention can have aduty cycle of greater than 1%. For example, in one embodiment thepushing ultrasound waves pulse for 100 microseconds every threemilliseconds. By comparison, lithotripsic ultrasound may run, forexample, for a 5 microsecond pulse, with a 250 millisecond durationbetween pulses, for a duty cycle of <1%.

In a preferred embodiment of the invention, the pushing ultrasound willhave a pulse duration of about 100 μs, a center frequency of about 2.3MHz, a pressure amplitude of about 15 MPa in situ, with bursts repeatedevery 3 ms, and the total duration of each push sequence being about 1s. In one embodiment of the invention, imaging pulses can be interleavedwithin the pushing pulses for real time imaging.

The pushing ultrasound facilitates movement of a stone; in oneembodiment such movement can be toward an exit location. The exit can bea natural exit of a duct, vessel, or organ, or created surgically. Thepushing ultrasound can be more focused when directed to a particularstone, or either weakly focused or unfocused if directed toward ageneral region of the body such as a kidney pole. For example, a kidneypole area may be suspected of containing very small stone fragments orstone dust which may be difficult to image. Such weakly focused orunfocused pushing ultrasound can be used to stir up the small fragmentsor dust and facilitate their removal from the pole of the kidney,without the risk of tissue injury that might be caused by shock wavelithotripsy.

In some aspects of the invention, an imaging system can be used tolocate the stones for the application of pushing ultrasound. In oneembodiment of the invention, such imaging can be accomplished by knownimaging techniques such as fluoroscopy. In other embodiments of theinvention, such imaging can be accomplished by the application of any ofvarious modes of detection ultrasound, as discussed in greater detailbelow.

Detection Ultrasound

As noted above, in one aspect the inventive system and method disclosedherein employ detection ultrasound to locate stones within an organ,duct, or vessel such as the kidney, wherein the ultrasound wavesreflected from a stone are preferentially selected and displayedrelative to ultrasound waves reflected off blood or tissue. Thedetection ultrasound used in connection with the present invention canbe based on B-mode ultrasound or Doppler ultrasound, or both.

Doppler ultrasound is a form of ultrasound that can detect and measureblood flow. There are several types of Doppler ultrasound. Color Doppleris a technique that estimates the average velocity of flow within avessel by color coding the information. The direction of blood flow isassigned the color red or blue, indicating flow toward or away from theultrasound transducer. Color Doppler can overlay color on a B-modeimage. Pulsed Doppler allows a sampling volume or “gate” to bepositioned in a vessel visualized on the gray-scale image, and displaysa graph of the full range of blood velocities within the gate versustime. The amplitude of the signal is approximately proportional to thenumber of red blood cells and is indicated, not in color, but simply asa shade of gray. Power Doppler depicts the amplitude, or power, ofDoppler signals rather than the velocity. This allows detection of alarger range of velocities and thus better visualization of smallvessels, but at the expense of directional and velocity information.

B-mode ultrasound is based on two-dimensional diagnostic ultrasoundpresentation of echo-producing interfaces in a single plane. B-modeultrasound is based on brightness modulation, in which bright dots on ascreen represent echoes, and the intensity of the brightness indicatesthe strength of the echo. As is known in the art, the Doppler ultrasoundcan be overlaid on an image created by B-mode ultrasound, such as toshow blood vessels which may appear as red or blue on the ultrasounddisplay.

Standard Doppler detection such as for detecting blood flow is based onsmall signals that change over time, that are coherent, and have apattern. At some point in the Doppler image processing, the signals fromblood encompass a relatively narrow band of higher frequency and loweramplitude, while ultrasound reflections from tissue such as vessel wallsand organ tissue encompass a relatively narrow band of lower frequencyand higher amplitude. When using Doppler ultrasound to detect motion ofblood, it is known in the art to use an optional “wall filter” whichelectronically filters from the reflected ultrasound signal the lowerfrequency, higher amplitude waves reflecting from the vessel walls. Whenusing Doppler ultrasound to evaluate blood flow, it known in the art toautocorrelate data from an ensemble of Doppler pulses, frames, orvolumes, in which patterns of coherent data with relatively smallchanges from pulse to pulse are retained and converted into an imagesignal, while pulse data that is not part of the coherent pattern isdeleted from the signal as unwanted “noise.”

Stones are strong scatterers and therefore reflect strong signals. Asignal reflected from stone can change on the next pulse more than asimilarly strong signal reflected from tissue. While the cause of thedifference in ultrasound reflective properties is not completelyunderstood, it is believed that this difference may be caused by theabruptness of the transition from soft tissue to hard stone, by motionof the stone, or by internal waves in the stone not present in softertissue. Rather than deleting these signals as unwanted electronic noiseas in ultrasound systems of the prior art, in the method and system ofthe present invention the reflected ultrasound signals are processedsuch that these strong signals are preferentially retained relative tothe narrow bands of coherent signals reflected from blood and tissue,and the retained signals are converted into an image on a display. Thus,in contrast to the prior art, the present invention detects stones asstrong signals that change over time, with significant change inamplitude that randomly appears in some frames but not others. In someembodiments of the invention these acoustic differences can beexacerbated by nonlinear responses of the front end electronics of theimager.

This feature of the invention in which reflections from stones arepreferentially selected and retained in an image display relative toreflections from blood or tissue can be used both with B-mode detectionultrasound and with Doppler detection ultrasound. Where the applieddetection ultrasound is Doppler ultrasound, the strong signals that arepreferentially selected and displayed as an image can be those reflectedwaves related to the “twinkling” artifact of ultrasound in which theobject being scanned appears brighter or with different colors on theimage display monitor.

In those embodiments of the invention in which the pushing ultrasound isused in conjunction with Doppler detection ultrasound, then it is afeature of one embodiment of the present invention that this twinklingartifact can be used to enhance visualization of the stone during theapplication of pushing ultrasound, thereby allowing for greater controland accuracy in directing the pushing ultrasound toward the stone to bemoved. In one embodiment of the invention, an ultrasound systemrecognizes the twinkling artifact on an ultrasound display and redirectssubsequent pulses of pushing ultrasound waves to more efficientlyfacilitate motion of the stone in a desired direction.

Unless the context clearly dictates otherwise, embodiments in one aspectof the invention may be used in other aspects of the invention, and canbe combined with each other.

FIG. 1 illustrates an exemplary use of pushing ultrasound applied tomove a kidney stone in accordance with the concepts disclosed herein. Ina pushing ultrasound therapy probe 10, an acoustic coupling 16 isattached to a therapy transducer 14 that is mounted to a handle 12. Alead 18 couples the transducer 14 to a power supply (not shown). In FIG.1, probe 10 is being used to apply pushing ultrasound to a kidney 24through a dermal layer 20 of a patient (not otherwise shown).

Probes capable of producing and receiving both detection ultrasound andpushing ultrasound and suitable for use in the present invention includethe C4-2 and P4-2 HDI scanheads commercially available from Philips/ATL,although the scope of the invention is not so limited.

While many different acoustic transducers are suitable for pushingultrasound applications, many ultrasound transducers exhibit a generallyconical-shaped beam 26. When probe 10 is positioned so that beam 26passes through the kidney, acoustic pressure moves a kidney stone from afirst position 30 a to a second position 30 b, closer to an exit 32which can be either naturally present or artificially introduced such asby surgery. By properly positioning probe 10, the user can control thedirection the kidney stone will move. It should be understood that inthe context of an artificial exit, the concepts disclosed herein can beused to reposition stones closer to artificially placed tubes/cathetersduring surgery, such that the method and system disclosed herein can beused intra-operatively.

Acoustic transducer 14 can have a fixed focal length, or a variablefocal length. Variable focal length transducers are generally moreuseful. In applications where a fixed focal length acoustic transduceris used for application of pushing ultrasound, acoustic coupling 16 canbe used to control the position of focal region of beam 26 relative tothe patient. If a relatively thicker acoustic coupling 16 is employed,the focal region will be disposed closer to dermal layer 20, while if arelatively thinner acoustic coupling 16 is employed, the focal regionwill penetrate further below the dermal layer and deeper into thesubcutaneous target. Thus, the thickness of acoustic coupling 16 can beused to control the position of the focal region relative to a patient'stissue. The transducer may also be a linear, curvilinear, or phasedarray and be able to steer the beam to push the stone off the axis ofthe transducer.

In FIG. 1, an ultrasound imaging probe 22 generates an image plane 28.Focal beam 26 and the kidney stone at positions 30 a and 30 b lie withinimage plane 28, so that the movement of the kidney stone can bevisualized in an ultrasound image provided by ultrasound imaging probe22 during therapy. In other embodiments of the invention, the source ofimaging ultrasound and the source of pushing ultrasound for moving thestone can be contained within a single probe housing. In still otherembodiments of the invention, one transducer having one or a pluralityof elements can be used to detect and push the stone. Suitabletransducers include the P4-2 or C4-2 HDI transducer from ATL/Philips.These are standard curvilinear and phased array probes for imaging.

FIG. 2 is a functional block diagram of a system for detecting andpushing in vivo objects such as kidney stones and kidney stonefragments. System 40 includes a detection ultrasound component 42, apushing ultrasound component 44, a control and processing component 46,a user interface 48, and a display 50. In other embodiments, a singleunit can provide both ultrasonic detection and ultrasound treatment.Where the detection ultrasound component 42 is a Doppler ultrasoundcomponent, then detection of the stone in vivo can use the twinklingartifact in Doppler imaging. Processing and control component 46 caninclude the power supplies required to energize the ultrasoundtransducers in detection ultrasound component 42 and pushing ultrasoundcomponent 44, or such components can be implemented separately.

In one aspect of the invention the user can interact with user interface48 to choose an area on the display on which the pushing ultrasound isto be focused. Thus the user can guide the repeated application ofpushing ultrasound in real time to urge the stone toward an exit. In oneaspect of the invention, the ultrasound system detects the motion of thestone and then sends a new pushing pulse to the new location, tocontinuously follow the stone on its movement toward an exit. Userinterface 48 can include a mouse or touch screen as are known in thecomputer and medical technology arts.

If desired, a separate processing and control component can be employedfor each of detection ultrasound component 42 and pushing ultrasoundcomponent 44. Displays are sometimes incorporated into conventionaldetection ultrasound components, and if desired such a display can beused in place of display 50. User interface 48 is employed at least tocontrol the pushing ultrasound component 44, enabling the operator toenergize that component as required to achieve the desired movement ofthe in vivo object. With respect to the operation of pushing ultrasoundcomponent 42, if desired, control and processing component 46 canoverride a command to trigger the pushing ultrasound component if thecontrol and processing component 46 determines that delivery ofadditional pushing ultrasound could undesirably damage tissue, such asmay occur due to thermal or mechanical effects). The processing andcontrol component can be implemented using a custom circuit (i.e., ahardware implementation, such as an application specific integratedcircuit) or a processor executing machine instructions stored in amemory (i.e., a software implementation, where the software is executedby a computing device, such as a desktop or laptop computer). Suchprocessing and control components are known to those of ordinary skillin the art.

FIG. 3 is a flowchart of exemplary steps for implementing the conceptsdisclosed herein. In representative block 50, detection ultrasound isused to visualize an in vivo object such as a kidney stone or kidneystone fragment. As discussed above, in an exemplary but not limitingembodiment, the twinkling artifact in Doppler ultrasound is used tovisualize the in vivo object. In a block 52, pushing ultrasound is usedto move the in vivo object in a desired direction. In general, thedesired direction will cause the in vivo object to move to a natural orartificial opening, facilitating clearance of the in vivo object. Insome exemplary embodiments, the in vivo object is a fragment of a kidneystone that was previously fragmented. In other exemplary embodiments,the in vivo object is a relatively large intact kidney stone that mustbe fragmented prior to removal.

Thus, in optional block 54, the in vivo object that has been movedcloser to an exit is fragmented to facilitate its removal. Any of theknown fragmentation techniques can be employed.

Example 1

In an empirical study to test the concepts disclosed herein, a pushingultrasound device was used to move a kidney stone fragment, with thegoal of facilitating passage. In one study, natural and artificialstones about 1-8 mm in length were surgically placed in the urine spacein pig kidneys. A new system was assembled and programmed to both imagestones and push stones. The system had the general design of FIG. 5Awhere the pulser/receiver and analog to digital converter box was aVerasonics Ultrasound Engine (Verasonics, Bothell Wash.). The transducerwas either a P4-2, P4-1, or C4-2 HDI transducer from ATL/Philips,Bothell Wash.).

FIG. 4 schematically illustrates the setup in the empirical study. Atissue phantom 68 (or live porcine kidney) with an embedded object wasprovided. A pushing ultrasound component 66 was coupled to the phantomusing a coupler 70. A detection ultrasound component 64 (a distal end 64a of which can be seen in the Figure), coaxially aligned with thepushing ultrasound component, was used to acquire images of the embeddedobject as it was moved in the tissue phantom/kidney by the pushingultrasound. A processing and control component 60 was used to controlthe ultrasound components, and the ultrasound image was presented to theuser on a display 62.

In the empirical studies, a research ultrasound device designed forother medical therapies was used, which combines a commercial ultrasoundimaging system with a research pushing ultrasound therapy system. Theimaging probe is placed within, looking down the axis of, the therapyprobe. In the empirical study, longer bursts of higher amplitude focusedultrasound were applied than are generally employed in diagnosticultrasound (30-ms, 10-MPa bursts repeated at 10 Hz). The force appliedto stone fragments and motion of the fluid around the stone caused stonemotion. Motion of natural and artificial stones was observed visually ina kidney phantom of transparent tissue mimicking gel surrounding awater-filled space, and with diagnostic ultrasound and fluoroscopy inlive and excised pig kidneys.

Stone velocities were on the order of 1 cm/s and stones quickly movedout of the ultrasound focus. Operators could generally control thedirection of stone movement.

In the empirical study, a sonographer using Doppler ultrasound and whatis known as “twinkling artifact” visualized stones as small as 1 mm inthe kidney of a porcine animal model. When pushing ultrasound wasapplied, these stones were seen on the real-time ultrasound display tojump up at −1 cm/s. While in some embodiments pushing ultrasoundexposure might result in thermal damage to tissue, no such damage wasnoted in the empirical study. The empirical study indicated that pushingultrasound can be used to move stones within a collecting system inorder to optimize rates of stone clearance.

It should be noted that while the present novel approach of movingkidney stones (or fragments thereof) using focused ultrasound representsan exemplary embodiment, the concepts disclosed herein can also be usedto move other embedded objects, including, but not limited to, stones,fragments and dust located in any of the gall bladder, the salivarytract, and the biliary tract of a human or other mammal.

The following Figures illustrate various modes of detection of stones inaccordance with the invention, in which like reference numerals indicatelike components. These various modes of detection can be used eitheralone or in combination with each other and a voting algorithm or withthe use of pushing ultrasound to facilitate stone clearance, asdiscussed above.

FIG. 5A is a schematic representation of a system suitable for use inthe present invention comprising a CPU 72, a combined ultrasoundpulser/receiver and analog to digital converter 73 operatively connectedto a transducer 74, a monitor display 75, and various means for operatorinput and control such as keyboard 76, mouse 77, and monitor touchscreen control 78, all of which are conventional in the computerizeddiagnostic arts. Transducer 74 can be used to apply detection and/orpushing ultrasound to a patient and to receive reflected ultrasoundsignals and transmit them back to CPU 72 for further processing asdescribed more fully below, and as shown schematically in FIG. 5B.

FIG. 5C is a flowchart of a method and system 80 of the prior art usingB-mode imaging ultrasound. Reflected ultrasound waves are received bythe transducer elements 81, and are converted to electrical signals. Theelectrical signals pass through one or more attenuators and/oramplifiers, collectively indicated at 82, and the amplified and/orattenuated signals are then transmitted to analog-to-digital converter83. From converter 83 the digitized signals pass to beam former 84, andthen to converter 85 where the signals are converted to either amplitudeor intensity. The converted are then transmitted to compression means86, where their values which range over a large scale (e.g., 1-100000)are remapped to a smaller scale (e.g., 1-256) according to some definedalgorithm. The compressed data are then displayed at display means 88.

FIG. 6 is a flowchart of an embodiment of the invention using B-modeultrasound and in which the more intense ultrasound signals reflectedfrom a stone, especially in contrast to less intense signals fromregions immediately adjacent to the stone, are preferentially selectedor enhanced relative to the less intense ultrasound reflections fromblood and tissue. This embodiment is based on the fact that stonesnormally appear brighter than tissue or blood on a B-mode ultrasoundimage because of the higher amplitude acoustic reflection from a stone,such that in this embodiment the reflected waves of higher amplitude aredisplayed in color to indicate the presence of a stone. In thisembodiment, the data from converter 85 is subjected to one of twospecific types of data compression. At compression means 90, the dataare subjected to either logarithmic or exponential compression over thefull range of the data input. At alternative compression means 92, thedata are subjected to alternative compression schemes which magnify thedifferences between intense signals, wherein the low end magnificationemphasizes tissue and the high end magnification emphasizes strongreflectors like stones, such that the mode of compression can beselected to emphasize stones. Those signals that reach a predeterminedthreshold of amplitude or intensity, typically about 95% of maximum, arethen interpreted as strong signals reflected from a stone, such that theCPU can operate to preferentially add color to the display of the stone,or add one color to the high amplitude (or intensity) signals toindicate stone and a different color to the low amplitude (or intensity)signals to indicate tissue.

FIG. 7 is a flowchart of an alternative embodiment of the inventionusing B-mode ultrasound and in which the more intense ultrasound signalsreflected from a stone, especially in contrast to less intense signalsfrom regions immediately adjacent to the stone, are preferentiallyselected or enhanced relative to the less intense ultrasound reflectionsfrom blood and tissue. This embodiment relies on the ultrasound“shadows” generated when ultrasound is reflected from a stone, such thebright spot of the reflection is immediately proximal to the darker spotwhich represents the shadow on the distal side of the stone. The data isanalyzed for this shadow artifact at data analyzer 94, wherein the stoneis identified by the adjacency of the bright and dark spots. In apreferred embodiment, the B-mode ultrasound is reapplied at differentexposure angles to confirm the presence of the shadow and therefore thepresence of the stone. In addition, the ultrasound beam can be modifiedas is known in the art in other ultrasound applications, for example toa broad plane wave, called in the art a flash, to quickly image thewhole field and enhance a shadow that can be obscured in a more focusedimaging beam. Once identification of the stone is confirmed theinformation is optionally stored in data storage means 96 and thegenerated image of the stone is labeled or otherwise enhanced at displaymeans 88 to indicate the presence of a stone to the operator.

FIG. 8 is a flowchart of an alternative embodiment of the inventionusing B-mode ultrasound and in which the more intense ultrasound signalsreflected from a stone, especially in contrast to less intense signalsfrom regions immediately adjacent to the stone, are preferentiallyselected or enhanced relative to the less intense ultrasound reflectionsfrom blood and tissue in which an image is created from the spatialderivative of the intensity map, such that the highest derivativesindicate the location of the stone. Data from or before compressionmeans 86 is processed at data analyzer 98 to take the spatialderivative, such that the abrupt change in brightness (high derivative)indicates the edge of a stone. These data are then merged with thecompressed data to generate an image displayed at display means 88.

FIG. 9 is a flowchart illustrating standard prior art methods of Dopplerultrasound. Doppler ultrasound is applied to the subject, the reflectedwaves are amplified or attenuated and digitized, and the information isstored at storage means 89.

This step may be repeated n−1 times to generate an ensemble of data atdata collection means 102. The ensemble of data is beam-formed at 84.The data in beam form are then demodulated into phase and amplitudecomponents at 104. As is known in the art, ultrasound that reflects offtissues such as vessel walls will have a higher amplitude thanultrasound that reflects off of blood. Also the tissue either is notmoving or is moving very slowly compared to blood, so at this point inthe processing the signals from tissue are lower frequency and thesignals from blood are higher frequency. Therefore wall filter 106removes the low frequency data from tissue, leaving only the datarelating to the presence of blood. The filtered data are then processedby autocorrelation at 108 to optimize the indication of blood in theimage at a predetermined threshold amplitude. A B-mode image which showsother pertinent features (i.e., anatomical structures) can be eithergenerated from the demodulated data at 110 or obtained from a separatedata source at 112. This B-mode image is then merged at 114 with theautocorrelated data from 108, such that a display is provided at 88comprising both the B-mode image of the surrounding anatomy and theDoppler image of the blood.

In the prior art methods of processing Doppler data, the data areprocessed to eliminate signals having higher amplitudes, largediscontinuities, outliers, and broad band twinkling effects, so thatblood and tissue are more readily seen. In each of the followingembodiments of the invention, the opposite approach is used, i.e., thosesignals that are generally discarded in prior art Doppler ultrasoundsystems are not only retained in the present invention but areaccentuated relative to the signals reflected from blood and tissue, tomore accurately identify the stones that generate such signals. Each ofthe embodiments of FIGS. 10-13 represents a different statisticalapproach to achieving this goal.

FIG. 10 is a flowchart of a modification of the method of FIG. 9 withthe additional step at 116 of multiplying one or more of the data sets,also known as frames, in an ensemble by a selected factor. In oneexemplary embodiment, raw data of fourteen frames is collected in anensemble and one or more of the individual frames is multiplied by afactor of about 1.05-1.1, such that the amplitude of the data in thatframe is amplified by about 5-10%. The reflections from the stoneswithin each frame vary more greatly and in a more random way from frameto frame than do the reflections from tissue or blood. This manifests ata point in the Doppler processing as broadband frequency or noisecompared to the low frequency from tissue and the narrow-band relativelyhigh frequency from blood. The broadband frequency or high randomvariability from stones causes the twinkling artifact. The 5-10%amplification to one frame amplifies the variability among or betweenframes to further draw out the high variability signals from stones soas to be readily identified at display means 88, thereby providing amore sensitive means for detecting stones.

FIG. 11 is another alternative embodiment of the stone detection methodof the invention using Doppler radiation and with the additional step ofdetecting relatively large changes particularly in amplitude, i.e.,“outliers,” within frames in the ensemble. In one aspect of thisembodiment of the invention, in place of a standard wall filter andautocorrelation the stone detection method is based on relatively largejumps of a single IQ pair in the Doppler ensemble for a pixel. This canbe done in several ways that will be recognized by those skilled in theart of statistical data analysis. For example, in one embodiment, ateach pixel the maximum amplitude is determined as max(signalIQ)−mean(signal IQ). In another mode, the z-score will be used toevaluate the data distribution, and the twinkling reflections aredetermined as outliers based on the number of standard deviationsoutside the expected range.

The selected values are normalized within the region of interest at step120; these values are then merged with a B-mode image and displayed atdisplay means 88.

FIG. 12 is a modification of the method of FIG. 11 wherein instead of adetermination of outliers there is at 122 a statistical determination ofthe variance of the data, where variance according to its mathematicaldefinition is determined as the amount of deviation left in the dataafter the mean is subtracted out. This statistical method retainssignals such as twinkling artifacts that are not close to the mean ofthe data, such that these signals are accentuated at display means 88.

FIG. 13 is a modification of the algorithm of FIG. 10 but in which anautoregression analysis is used rather than an autocorrelation of theDoppler data. This embodiment can be operated in two different modes. Inone mode of operation of this embodiment, the demodulated data from step104 is processed by a wall filter to remove data relating to reflectionsfrom tissue. The data is then subjected to a first or higher orderautoregression analysis to identify coherent signals from blood flow. Inthe alternate mode of operation, no wall filter is used, but the dataundergoes a second or higher order autoregression analysis at 126 toidentify coherent signals from tissue and blood flow. In either mode ofoperation, the autoregression analysis suppresses coherent signalsleaving only noise over a broad spectrum. The analyzed data is thensubjected to a threshold determination such that the signals with thehigher noise power are considered to be the twinkling signals and aredisplayed with the B-mode ultrasound image on the display 88.

Another aspect of the invention relates to a method for determining theoutput voltage and threshold level. In considering the distribution ofthe calculated twinklepower, as the output voltage for the systemincreases, the distribution of the non stone pixels shifts lower, whilethe stone pixels remain at the high end of the range. The threshold fordisplay can be set at the high end of the non-stone distribution, butbelow the stone threshold. This method works because as the outputvoltage is increased, the tissue signal-to-noise ratio increases and isbetter filtered by the wall filter, while the effect that causes thestone to twinkle remains.

In one embodiment of one aspect of the invention, any one or more ofimage processing techniques such as 2D cross-correlation, phasecorrelation, and feature-edge detection are used to overlay color on thestone in the real-time, B-mode images and to assign a color to indicatethe confidence in the identification of the stone.

In another embodiment the system can detect a moving stone, re-targetthe pushing ultrasound, and apply a new focused push pulse at thatlocation.

It will be recognized by those skilled in the art that any combinationof detection algorithms can be combined using a decision matrix tooptimize the location of the stone. Also variations of the above methodswill be recognized by those skilled in the art. For example, in any ofthe illustrated embodiments, the beam forming at 84 could be analog beamforming that would then occur prior to digitization. Beam forming alsocould occur within the ensemble collection loop. Similarly, in each ofthe foregoing embodiments the system makes a threshold determination asto which information to display at each pixel of display means 88,unless a multi-dimensional color map or semi-transparent layers areused. In the embodiments illustrated herein, the threshold determinationis based on the B-mode power and the noise power. Those skilled in theart will recognize that such a threshold determination also could bemade on the basis of traditional Doppler power, velocity, variance,higher order moments, or other information that can be obtained from theautoregression model.

It also will be appreciated that any of the detection methods of thepresent invention as illustrated in FIGS. 6-8 and 10-13 and describedabove can be practiced in conjunction with other aspects of thisinvention, in particular with other data analysis aspects of theinvention, or with or without the use of pushing ultrasound to move astone. The detection methods disclosed herein can be used either todisplay an image of a stone, or to provide an aural or other indicationof the presence and/or location of a stone.

The system described in Example 1 above also was used to perform all thesame experiments described in Example 2. The system was operated withthe following parameters:

Push Pulse Frequency 2.3 MHz Dependent on transducer Push Pulse length0.1 msec Determined empirically Push Pulse Frame rate 15 frames/secondCould be increased if necessary Push Pulse time 1 second Limited toprevent transducer damage Charge Time 3.0 msec Determined empiricallyImaging time 2.5 msec Dependent on imaging depth # of pushes/frame 21Dependent on imaging time, push time, charge time and frame rate PushPulse Duty cycle 3.15% Total CLEAR time/ duration of 1 frame

Detection of the fragment was achieved using the imaging describedabove, B-mode ultrasound, and the twinkling artifact produced by thestones/fragments in Doppler mode ultrasound. In this empirical study,the same elements in the transducer were used for both imaging andpushing. Ultrasound and fluoroscopy showed the stones moving inreal-time under the influence of the pushing ultrasound. Stones moved onthe order of 1 cm/s away from the source, and several stones movedseveral centimeters down the ureter. It appeared that such movement wasonly induced when the stones/fragments were directly in the path of thefocal beam, indicating that radiation pressure, as opposed to streaming,caused the motion. While ultrasound imaging and fluoroscopy were usedindependently in this study to track the initial position and motion ofthe stone/fragments being moved by the pushing ultrasound, other imagingmodalities could be employed. Such imaging modalities include, withoutlimitation, fluoroscopy, computed tomography (CT), low-dose stoneprotocol CT, B-mode ultrasound, magnetic resonance imaging (MRI), andDoppler ultrasound. When Doppler ultrasound is used the twinklingartifact may make the stones appear brightly colored in the imagedisplay. The methods and systems disclosed herein can be adapted to usethe twinkling artifact to facilitate visualization of the stones fordiagnosis and treatment.

Example 2

The system used in the Examples is shown in FIG. 14 in which (a) is adiagram and (b) is a photograph of the ultrasound system. It consistedof a 6 cm dia., 2 MHz, eight element annular array curved to a naturalfocus of 6 cm (Sonic Concepts model H-106, Bothell, Wash.). The eightelements were excited by the synchronized outputs of 8 signals from anSC-200 radiofrequency synthesizer (Sonic Concepts, Bothell, Wash.) andamplified by eight 100 W amplifiers (Icom IC-706MKIIG, Bellevue, Wash.).A laptop computer controlled the timing of the excitation of eachelement, which allowed the focal depth to be varied from 4.5-8.5 cm. Thecomputer also collected the image from the ultrasound imaging system(HDI-5000, Philips/ATL, Bothell, Wash.) and overlaid on the image theuser selected focusing depth so the user could visually align the stoneat the focus. The probe of the imager (P4-2) looked through the apertureof the therapy array and was within a water-filled coupling head muchlike a shock wave lithotripter but smaller and held in the hand of theuser. The electronics and probe with the longer coupling cone are shownin the photograph. The ultrasound imager is not shown. A footswitchswitch turned the focused ultrasound such that it was on for about 50 msand off for about 50 ms while the switch was closed. Interferenceobscured the imaging while the focused ultrasound was on but properlysynchronized pulsing permitted the half of the image containing thestone to remain obscured. Total exposure in a burst of pulses was 1-4 s,and no more than 10 bursts were used to move one stone. The acousticbeam is shaped as an hourglass with the greatest energy concentrationand highest pressures in the narrow focus region. The region over whichthe pressures are within half of the peak pressure is only 1 cm long andabout 1 mm wide. Time-averaged acoustic intensities, measured in waterand derated to the 6.5 cm penetration depth in tissue were 250, 500, and1000 W/cm².

All animal studies were acute, and animal research procedures wereapproved by the University of Washington IACUC. Twelve common domesticfemale pigs (age five months and 50-60 kg) underwent induction ofgeneral anesthesia, had their flank regions shaved and depilated, andwere secured to the operation room table. In six pigs, artificial stones(radio-opaque glass/metal beads 3 and 5 mm in diameter) and humanurinary stones (cystine, calcium oxalate monohydrate, or calciumhydrogen phosphate dihydrate, 1-8 mm) were endoscopically placed intothe lower pole using retrograde ureteroscopy, retrograde percutaneousnephrolithomy or open surgical access and canalization of the ureter. Aretrograde pyelogram was performed to outline the porcine collectingsystem. Prior the treatment with focused ultrasound, stone position wasvisually confirmed endoscopically and fluoroscopically. Most stones wereplaced in the lower pole but many were placed in upper pole calyces.

Both kidneys were accesses through open surgery in the other sixanesthetized pigs. A longer coupling cone was added the array to placethe focus 0.5-1 cm beyond the end of the cone. The abdomen was filledwith saline to ensure coupling, and the cone was placed in directcontact with the kidney. Five regions on each kidney were targeted, andthe surface location marked with ink. Control regions of the kidneyreceived no ultrasound exposure. Other regions received two minute totalexposure at 50% duty cycle at time averaged intensities 325 and 1900W/cm². The pigs were sacrificed, and the kidneys were harvested. Bothkidneys were freshly sectioned for gross examination, and samplesembedded for histological analysis. Microscopic examination wasperformed using serial sections stained with hematoxylin and eosin (H&E)and nicotinamide adenine dinucleotide-diaphorase (NADH-d). Any signs ofthermal or mechanical injury to the renal parenchyma were assessed byobservers blinded to the exposure conditions.

FIGS. 15A and 15B show super-imposed frames of a fluoroscopic movietracking the ultrasonic expulsion of a bead. The fluoroscopic imageshows the 5-mm bead moved roughly 3 cm in 1.3 s traveling from the lowerpole through the UPJ into the ureter. A single ultrasound burst pushedthe 5-mm bead from the lower pole to the UPJ where it is bounced andfell into the canalized ureter. The beads are denser and much moreradio-opaque and therefore easier to observe in the fluoroscopic imagesthan the human kidney stones that were used. The bead moved severalcentimeters in 1.1 s. The duration of the ultrasound burst was only 1 sand more importantly the ultrasound energy is concentrated into a regiononly 1 cm long. The impulsive push of the stone was sufficient to makethe bead move beyond the ultrasound focus. Stones or beads were moved tothe renal pelvis and ureteropelvic junction (UPJ) in all six pigs. Nomore than ten minutes per stone were required, and total exposures tofocused ultrasound were shorter than two minutes. Average velocity ofstone movement was about 1 cm/s and stones traveled on average about 1cm with each effective 1 s propulsion pulse.

Most of the effort was visualizing the stone at an appropriate angle topush it into a fluid space toward the UPJ. Angles of focus that wereparallel to the axis of the infundibulum resulted in larger displacementof the stone. Stone motion was not observed at all angles of focusedultrasound delivery, but often if stones were pushed toward a tissueinterface the stone ricocheted in a direction along the interface.Larger fluid spaces made propulsion easier. Stones were repositioned atall acoustic intensities used: previous in vitro experiments were notsuccessful with lower intensities. It was not observed that a stone wassuddenly made to move simply by increasing the power or that stonesmoved faster with more power. We concluded that the difficulty in movingthese stones was primarily due to alignment of the narrow focus on thestone at an appropriate angle.

FIGS. 16A-16C show representative histology slides from a control, andexposure to 325 W/cm² and exposure to 1900 W/cm². Specifically, theviews are hematoxylin and eosin and nicotinamide adenine dinucleotidestained sections of porcine kidney (a) not exposed to ultrasound (b)exposed to levels used in the ultrasonic propulsion of stones, and (c)exposed to levels above those used for stone propulsion. Thermal injuryis shown in image (c). The bar represents 100 μm. Control and the samplefrom the 325 W/cm² exposure are similar and show no apparent injury. Thesample from the 1900 W/cm² exposure contains damaged regions consistentwith thermal coagulation, as evidenced by shrinkage of the cells andincreased intensity of eosinophilic staining. The NADH-d stained serialsection confirmed thermal damage in the 1900 W/cm² exposure sample asindicated by the lack of staining. None of the three control samples orfive samples from the 325 W/cm² exposure showed any evidence of injurythermal or otherwise. Six of the seven samples from the 1900 W/cm²exposure showed thermal injury, but the lesion created was localized towithin 1 cm in its longest dimension. Thus, a threshold for injuryexists, but it appears to be above the level required to move stones.

Although the concepts disclosed herein have been described in connectionwith the preferred form of practicing them and modifications thereto,those of ordinary skill in the art will understand that many othermodifications can be made thereto. Accordingly, it is not intended thatthe scope of these concepts in any way be limited by the abovedescription.

While illustrative embodiments have been illustrated and described, itwill be appreciated that various changes can be made therein withoutdeparting from the spirit and scope of the invention.

The invention claimed is:
 1. A non-lithotriptic method for moving astone in a living body, comprising displacing the stone by generating aplurality of pulses of ultrasound radiation to push the stone in vivowithout fragmenting the stone, the ultrasound radiation imparting atransfer of momentum to the stone resulting in displacement of the stonewithout causing thermal or mechanical damage to surrounding tissue,wherein the plurality of pulses have a spatial peak temporal averageintensity I_(SPTA) in the range of 3 W/cm² to 325 W/cm² (325W/cm²>I_(SPTA)>3 W/cm²), wherein the plurality of pulses have a pressureamplitude in the range of 5 MPa to 30 MPa.
 2. The non-lithotripticmethod of claim 1, wherein the plurality of pulses have a spatial peaktemporal average intensity greater than about 4 W/cm² (I_(SPTA)>⁴W/cm²).
 3. The non-lithotriptic method of claim 1, wherein the pluralityof pulses each have a pulse duration of greater than 2.2 ms.
 4. Thenon-lithotriptic method of claim 1, wherein the plurality of pulses eachhave a pulse duration of about 50 ms.
 5. The non-lithotriptic method ofclaim 1, wherein the stone is exposed to the plurality of pulses for acumulative time of less than about two minutes.
 6. The non-lithotripticmethod of claim 5, wherein the plurality of pulses are generated withina continuous time period of less than about ten minutes.
 7. Thenon-lithotriptic method of claim 1, wherein the plurality of pulses eachincludes an ultrasound wave oscillating at a frequency that is greaterthan or equal to 0.25 MHz and less than or equal to 1 MHz.
 8. Thenon-lithotriptic method of claim 1, wherein the plurality of pulses eachincludes an ultrasound wave oscillating at a frequency that is greaterthan or equal to 1 MHz and less than or equal to 5 MHz.
 9. Thenon-lithotriptic method of claim 1, wherein the plurality of pulses eachincludes an ultrasound wave oscillating at a frequency of about 2.3 MHz.10. The non-lithotriptic method of claim 1, wherein the plurality ofpulses each includes at least 5 oscillation cycles of an ultrasoundwave.
 11. The non-lithotriptic method of claim 1, wherein the pluralityof pulses each includes at least 10 oscillation cycles of an ultrasoundwave.